Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin

Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health. Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode-of-action, but for which resistance has surprisingly been widely reported but unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in liver disease patients, causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterised operon ( prdRAB ) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. Alarmingly, VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered ‘low-risk’ for antibiotic resistance development. Our study shows this assumption is flawed and widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics.